The present invention relates generally to ophthalmic compositions. In particular, the present invention relates to the use of a polymeric quaternary ammonium compound and boric acid to provide preserved, storage-stable ophthalmic compositions of acidic drugs.
Ophthalmic formulations generally contain one or more active compounds along with excipients such as surfactants, comforting agents, complexing agents, stabilizers, buffering systems, chelating agents, viscosity agents or gelling polymers and anti-oxidants. Ophthalmic formulations which are intended for multidose use require a preservative.
Organo-mercurials have been used as preservatives in ophthalmic formulations including ophthalmic solutions of acidic drugs. These organo-mercurials include thimerosal, phenylmercuric acetate and phenylmercuric nitrate. Organo-mercurials, however, have limitations due to potential mercury toxicity and poor chemical stability.
Sorbic acid, has also been used to preserve ophthalmic formulations, but it too possesses poor chemical stability as well as poor antimicrobial activity.
Benzalkonium chloride is a widely used preservative in ophthalmic solutions. However, benzalkonium chloride and other quaternary ammonium compounds are generally considered to be incompatible with ophthalmic compositions of drugs with acidic groups, such as nonsteroidal antiinflammatory drugs ("NSAIDS"). These preservative lose their ability to function as they form complexes with the charged drug compounds.
U.S. Pat. No. 5,110,493 discloses stable ophthalmic NSAID formulations which do not contain organo-mercurial preservatives. Instead, the reference NSAID formulations use quaternary ammonium compounds, such as cetyltrimethylammonium bromide, cetylpyridinium chloride and preferably, benzalkonium chloride, and a stabilizing amount of a nonionic surfactant.
PCT application WO 94/15597 discloses the use of lauralkonium chloride, the C.sub.12 homolog of benzalkonium chloride, in ophthalmic formulations of drugs which are incompatible with benzalkonium chloride. Unlike the mixture of alkyldimethylbenzylammonium chloride known as benzalkonium chloride, this PCT application discloses that lauralkonium chloride is compatible with acidic drug entities; apparently it does not form insoluble ion complexes with the charged drug compounds.
In some cases, the present lack of a single preservative which is safe, stable, and able to meet both the United States Pharmacopoeia (USP) and European Pharmacopoeia (Ph. Eur.) preservative effectiveness requirements for ophthalmic formulations of acidic drugs has forced pharmaceutical companies to develop more than one formulation of the same drug, with each formulation containing a different preservative.
U.S. Pat. No. 4,960,799 discloses storage stable aqueous ophthalmic compositions containing diclofenac, a nonsteroidal antiinflammatory drug, and/or its pharmaceutically acceptable salts. The reference compositions include EDTA as a stabilizing agent, a solubilizer such as polyethoxylated castor oil, and a bacteriostat. The preferred bacteriostats are thimerosal and sorbic acid. No mention is made of any polymeric quaternary ammonium preservative.
The use of POLYQUAD.RTM. and other polymeric quaternary ammonium compounds as a disinfectant and preservative in contact lens care and artificial tear solutions is known. See, for example, U.S. Pat. Nos. 5,037,647; 4,525,346; and 4,407,791.
U.S. Pat. No. 4,525,346, in addition to disclosing applications in contact lens and artificial tear solutions, also discloses the use of certain polymeric quaternary ammonium compounds in formulations containing certain ophthalmic drugs. However, neither this reference nor any of the other references mentioned above discloses the use of a polymeric quaternary ammonium compound as a preservative in formulations of acidic ophthalmic drugs, that is, drugs which may be incompatible with positively charged preservatives.